Absorbable crystalline polyether-ester-urethane-based bioactive luminal liner compositions

ABSTRACT

Bioactive hydroforming luminal liner compositions are formed of an absorbable crystalline amphiphilic polyether-ester-urethane dissolved in a liquid derivative of a polyether glycol that undergoes transformation into a tissue-adhering, resilient interior cover or liner for the controlled release of its bioactive payload at clinically compromised conduits in humans as in the case of bacteria- and yeast-infected vaginal canals, esophagi, and arteries following angioplasty.

The present application claims the benefit of prior provisionalapplication, U.S. Ser. No. 61/211,800, filed Apr. 3, 2009.

FIELD OF THE INVENTION

The present invention is directed to absorbable, crystalline,polyether-ester-urethane-based compositions that can be delivered to theluminal wall of a body cavity or conduit of the gastrointestinal tract,urinogenital or vascular systems to form a bioactive, adhering linerupon contacting the respective wet luminal surface, wherein thebioactivity of the liner is associated with the controlled release of atleast one bioactive agent selected from the group consisting ofantimicrobial, antiviral, immunosuppressant, antineoplastic, andanti-inflammatory agents. The bioactive luminal liners are applicablefor use in treating vaginal and esophageal fungal infections and furtherin preventing vascular restenosis following angioplasty and treatingurinogenital infections.

BACKGROUND OF THE INVENTION

Polyurethanes represent a main class of synthetic elastomers employedfor long-term, medical implants as they present tunable chemicalproperties, excellent mechanical properties, good blood compatibility,and also can be designed to degrade in biological environments [A.Rechichi et al., J. Biomed. Mater. Res., 84-A, 847 (2008)]. Morespecifically, polyether-urethane (PEU) and polyether-urethane-urea(PEUU) elastomers have long been considered ideal for use in manyimplanted devices, in spite of occasionally cited drawbacks [M. A.Schubert et al., J. Biomed. Mater. Res., 35, 319 (1997); B. Ward et al.,J. Biomed. Mater. Res., 77-A, 380 (2008)]. Of the cited drawbacks arethose associated with (1) the generation of aromatic diamines, which areconsidered to be toxic upon degradation of segmented copolymers madeusing aromatic diisocyanates for interlinking; (2) chain degradation dueto oxidation or radiation degradation of the polyether component ofsegmented copolymers, and particularly those which encounter frequentmechanical stresses in the biological environment; and (3) chemicaldegradation in chemically and mechanically hostile biologicalenvironments of the urethane links of segmented copolymers andparticularly those comprising reactive aromatic urethane linkages.

Liquid solventless, complex polymeric compositions, which thermoset atambient temperatures through additional polymerization of atwo-component system, wherein the first component comprises amine oracrylate-terminated polyurethanes or polyurethane-ureas and the secondcomponent comprises di- or polyacrylates have been described in U.S.Pat. No. 4,742,147. However, the prior art is virtually silent onself-standing PEU and PEUU liquid solventless compositions for use inpharmaceutical formulations and/or medical devices. Similarly, the priorart on polyether-urethanes is practically silent on hydroswellable (orwater-swellable) systems, in spite of the fact that it addresseselastomeric, segmented, hydrophilic polyether-urethane-based, lubriciouscoating compositions based on aromatic diisocyanate and polyethyleneglycol (U.S. Pat. No. 4,990,357)—it did not suggest a self-standingmaterial for medical device applications. This prompted a study subjectof a recent disclosure by one inventor of the instant invention and hiscoworkers (U.S. patent application Ser. No. 12/380,391). The latterdisclosure dealt in general with hydroswellable, absorbable andnon-absorbable, aliphatic, segmented polyurethanes and polyurethane-ureacapable of swelling in the biological environment with associatedincrease in volume of at least 3 percent have more than one type ofsegments, including those derived from polyethylene glycol and themolecular chains are structurally tailored to allow the use ofcorresponding formulations and medical devices as carriers for bioactiveagents, rheological modifiers of cyanoacrylate-based tissue adhesives,as protective devices for repairing defective or diseased components ofarticulating joints and their cartilage, and scaffolds for cartilagetissue engineering.

Most pertinent to the instant invention are certain composition andformulations described in U.S. patent application Ser. No. 12/380,391,which can be used as (1) injectable gel-forming liquid formulations forthe controlled delivery of bioactive agents for treating periodontitis,nail infections, bone infections, a variety of bacterial and fungalinfections, and different forms of cancers, and (2) in situ-forming,extrudable luminal liner for the controlled drug delivery at the luminalwall of vaginal canals and blood vessels. However, the use of thesecompositions as covers or liners on the luminal wall of vaginal canals,esophagi, and blood vessels may be less than optimum since the teachingof U.S. patent application Ser. No. 12/380,391 deals mostly withhydroswellable amorphous coatings, which may undergo excessivedeformation and creep in presence of low levels of shear stresses. Thisprompted the study, subject of the present invention, which relates to anew class of absorbable crystalline polyether-ester-urethane-basedcompositions, which represent a substantial improvement over theiramorphous analogs of the prior art, in terms of providing a set ofbalanced properties that support hydroformation into tissue-adheringliners that are not only resilient, but also resist deformation in thepresence of shear forces.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed to a bioactivehydroforming luminal liner composition comprising at least oneabsorbable crystalline amphiphilic polyether-ester-urethane having amolecular weight of at least 10 kDa, preferably at least 20 kDa, morepreferably at least 35 kDa, most preferably at least 50 kDa, and a heatof fusion exceeding 5 J/g, preferably exceeding 10 J/g, more preferablyexceeding 20 J/g, most preferably exceeding 30 J/g, a liquid derivativeof a polyether glycol and at least one bioactive agent selected from thegroup consisting of antimicrobial, antiretroviral, antiviral,antiretroviral, anti-inflammatory, antiproliferative, immunosuppressing,antineoplastic, and anesthetic agents, wherein the at least oneabsorbable crystalline polyether-ester-urethane is the reaction productof at least one polyalkylene glycol, end-grafted with at least onecyclic monomer selected from the group consisting of ε-caprolactone,p-dioxanone, a lactide, glycolide, 1,5dioxapan-2-one, trimethylenecarbonate, and a morpholinedione. The resulting end-grafted product isfurther interlinked with a diisocyanate, wherein any unreactedisocyanate group is converted to a urethane group through reacting withan aliphatic alcohol, and wherein the absorbable crystallinepolyether-ester-urethane is the reaction product of a polyethyleneglycol having a molecular weight of 3 to 35 kDa end-grafted with atleast one cyclic monomer selected from the group consisting ofε-caprolactone, p-dioxanone, a lactide, glycolide, 1,5dioxapan-2-one,trimethylene carbonate, and a morpholinedione. The resulting end-graftedproduct is further interlinked with at least one aliphatic diisocyanateselected from the group consisting of 1,4-tetramethylene diisocyanate,1,4-bis(methylene isocyanato) cyclohexane, 1,6-hexamethylenediisocyanate, and lysine diisocyanate, and any unreacted isocyanate isconverted to a urethane group through reacting with 2-propanal, andfurther wherein the at least one bioactive agent is an antifungal agentselected from the group consisting of ketoconazole, miconazole,voriconazole, and fluconazole. The respective antifungal formulation canbe used for treating vaginal yeast infection in humans using anapplicator kit for delivering the active formulation which includes asolid applicator in a tubular housing of slightly larger diameterwherein the applicator has clockwise, helical grooves 2 mm in width anddepth and both the applicator and tubular housing are threaded at theirends to allow secure assembling of the kit.

A second major aspect of this invention deals with a bioactivehydroforming luminal liner composition comprising at least oneabsorbable crystalline amphiphilic polyether-ester-urethane having amolecular weight of at least 10 kDa, preferably at least 20 kDa, morepreferably at least 35 kDa, most preferably at least 50 kDa, and a heatof fusion exceeding 5 J/g, preferably exceeding 10 J/g, more preferablyexceeding 20 J/g, most preferably exceeding 30 J/g, a liquid derivativeof a polyether glycol and at least one bioactive agent selected from thegroup consisting of antimicrobial, antiretroviral, antiviral,antiretroviral, anti-inflammatory, antiproliferative, immunosuppressing,antineoplastic, and anesthetic agents, wherein the at least oneabsorbable crystalline polyether-ester-urethane is the reaction productof at least one polyalkylene glycol, end-grafted with at least onecyclic monomer selected from the group consisting of ε-caprolactone,p-dioxanone, a lactide, glycolide, 1,5dioxapan-2-one, trimethylenecarbonate, and a morpholinedione. The resulting end-grafted product isfurther interlinked with a diisocyanate, and any unreacted isocyanategroup is converted to a urethane group through reacting with analiphatic alcohol, and wherein the absorbable crystallinepolyether-ester-urethane is the reaction product of a polyethyleneglycol having a molecular weight of 3 to 35 kDa end-grafted with atleast one cyclic monomer selected from the group consisting ofε-caprolactone, p-dioxanone, a lactide, glycolide, 1,5dioxapan-2-one,trimethylene carbonate, and a morpholinedione and again the resultingend-grafted product is further interlinked with at least one aliphaticdiisocyanate selected from the group consisting of 1,4-tetramethylenediisocyanate, 1,4-bis(methylene isocyanato) cyclohexane,1,6-hexamethylene diisocyanate, and lysine diisocyanate, and anyunreacted isocyanate is converted to a urethane group through reactingwith 2-propanal, and further wherein the at least one liquid derivativeof a polyether glycol is selected from the group consisting of acylatedpolyethylene glycol, benzylated polyethylene glycol, o-alkylatedpolyethylene glycol, o-benzylated polyethylene glycol, acylatedcopolymers of ethylene and propylene oxide, benzylated copolymer ofethylene and propylene oxide and benzylated copolymer of ethylene andpropylene oxide.

A third major aspect of the instant invention deals with a bioactivehydroforming luminal liner composition comprising at least oneabsorbable crystalline amphiphilic polyether-ester-urethane having amolecular weight of at least 10 kDa, preferably at least 20 kDa, morepreferably at least 35 kDa, most preferably at least 50 kDa, and a heatof fusion exceeding 5 J/g, preferably exceeding 10 J/g, more preferablyexceeding 20 J/g, most preferably exceeding 30 J/g, a liquid derivativeof a polyether glycol and at least one bioactive agent selected from thegroup consisting of antimicrobial, antiretroviral, antiviral,antiretroviral, anti-inflammatory, antiproliferative, immunosuppressing,antineoplastic, and anesthetic agents, wherein the at least oneabsorbable crystalline polyether-ester-urethane is the reaction productof at least one polyalkylene glycol, end-grafted with at least onecyclic monomer selected from the group consisting of ε-caprolactone,p-dioxanone, a lactide, glycolide, 1,5dioxapan-2-one, trimethylenecarbonate, and a morpholinedione, the resulting end-grafted product isfurther interlinked with a diisocyanate, and any unreacted isocyanategroup is converted to a urethane group through reacting with analiphatic alcohol, and wherein the absorbable crystallinepolyether-ester-urethane comprising the reaction product of apolyethylene glycol having a molecular weight of 3 to 35 kDa end-graftedwith at least one cyclic monomer selected from the group consisting ofε-caprolactone, p-dioxanone, a lactide, glycolide, 1,5dioxapan-2-one,trimethylene carbonate, and a morpholinedione, the resulting end-graftedproduct is further interlinked with at least one aliphatic diisocyanateselected from the group consisting of 1,4-tetramethylene diisocyanate,1,4-bis(methylene isocyanato) cyclohexane, 1,6-hexamethylenediisocyanate, and lysine diisocyanate, and any unreacted isocyanate isconverted to a urethane group through reacting with 2-propanal, andfurther wherein the at least one bioactive agent is an antibacterialagent selected from the group consisting of metronidazole, clindamycin,doxycycline, and tobramycin. The respective antibacterial formulationcan be used for treating vaginal and esophageal bacterial infections inhumans.

A clinically important aspect of this invention deals with the use ofthe subject polymers as carriers for treating (a) steroid-responsivedermatitis using hydrocortisone or triamcinolone; (b) septic arthritisand osteomyelitis using vancomycin or methylprednisolone; and (c)vaginal, esophageal or nail infection using ketoconazole, miconazole,terbinafine or voriconazole.

From a technological perspective, the antifungal and antibacterialformulation, subject of this invention, further include a method ofpreparation, sterilization, and packaging entailing the steps of (a)dissolving the crystalline polyether-ester-urethane in the liquidderivative of a polyether glycol; (b) heat-sterilizing the liquidsolution; (c) mixing the sterilized liquid solution with the antifungalor antibacterial agent, under aseptic conditions; (d) transferring analiquot of active formulation from step “c” to a pre-sterilized plastictubular housing of the applicator and securing the applicator in thehousing; (e) placing the assembled applicator kit from step “d” in asealable clear plastic pouch; and (f) heat-sealing the plastic pouchfrom step “e.”

From a clinical perspective, the intravaginal application of theantifungal and antibacterial formulation, subject of this inventionrequires an applicator kit for delivering the active formulationcomprising a solid applicator in a tubular housing of slightly largerdiameter wherein the applicator has clockwise, helical grooves 2 mm inwidth and depth, both the applicator and tubular housing are threaded attheir ends to allow secure assembling of the kit. Meanwhile, a methodfor application of said antifungal formulation onto the mucosal liningof the vagina of a human entails the steps of (a) removing theapplicator loaded with the liquid drug-loaded formulation; (b) insertingthe applicator into the vaginal canal using a clockwise, inwardmovement; and (c) removing the applicator from the vaginal canal using acounter-clockwise, outward movement.

A fourth major aspect of this invention deals with a bioactivehydroforming luminal liner composition comprising at least oneabsorbable crystalline amphiphilic polyether-ester-urethane having amolecular weight of at least 10 kDa, preferably at least 20 kDa, morepreferably at least 35 kDa, most preferably at least 50 kDa, and a heatof fusion exceeding 5 J/g, preferably exceeding 10 J/g, more preferablyexceeding 20 J/g, most preferably exceeding 30 J/g, a liquid derivativeof a polyether glycol and at least one bioactive agent selected from thegroup consisting of antimicrobial, antiretroviral, antiviral,antiretroviral, anti-inflammatory (steroidal and non-steroidal),antiproliferative, immunosuppressing, antineoplastic, and anestheticagents, wherein the at least one bioactive agent is one or two agentscapable of preventing restenosis following arterial angioplasty, andwherein preventing restenosis is effected by a combination of ananti-inflammatory agent and a second agent selected from the groupconsisting of antiproliferative, antineoplastic, immunosuppressing, andantimicrobial agents, and further, wherein the anti-inflammatory agentis naproxen, the antineoplastic agent is paclitaxel or curcumin and theimmunosuppressing agent is rapamycin. From a clinical perspective, theeformulations require the use of an applicator kit, similar to those usedin endovascular stent deployment, for delivering the active formulationcomprising an inflatable inner catheter inside a blind catheter withmultiple holes in the axial wall for the extrusion of the liquidformulation onto the luminal wall upon inflating the inner catheter.Meanwhile, a method of preparation, sterilization, and packaging thecatheter components of the applicator kit, entailing the steps of (a)dissolving the crystalline polyether-ester-urethane in the liquidderivative of a polyether glycol; (b) heat-sterilizing the liquidsolution; (c) mixing the sterilized liquid solution with the bioactiveagent or agents under aseptic conditions; (d) transferring an aliquot ofthe active formulation from step “c” into the blind end of the outsidecatheter; (e) inserting the inflatable inner catheter inside the outerone up to the point preceding the holed zone of the blind catheter; and(f) incorporating the two-catheter kit into a modified deployment kitfor endovascular stents.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In a major aspect the present invention is directed to the treatment ofvaginal and esophageal candidiasis. Vaginal Candidiasis (VC) is a commonmedical problem in women and is associated with discomfort, particularlydue to a copious discharge, which is often accompanied by odor.Currently available treatments of yeast infection include (1) a systemicoral administration therapy; (2) use of topical creams; and (3) use ofintravaginal suppositories which release the drug after melting ordissolving in the vagina. However, the systemic administration can leadto drug toxicity, while all other currently used forms for intravaginaladministration are subject to uncontrolled leakage of the drug duringthe vaginal discharge, creating unsanitary conditions and discomfortwhile resulting in unpredictable bioavailability of the drug. Esophagealcandidiasis (EC) is another form of fungal infection caused in mostcases by a candida species and results in sore throat and difficulty inswallowing. This infection is becoming more serious with the growingnumber of HIV patients who are highly susceptible to yeast infection.The orally administered treatment options of EC using oral formulationsare particularly effective in HIV patients. However, there have beenconcerns about the clinical relapse in these patients, which isdependent upon the degree of immunosuppression apart from the potentialhepatotoxicity associated with high or prolonged doses of orallyadministered drugs. Clinical shortcomings of the current treatments ofVC and EC evoked the need to explore the development of topicallyadministered drug delivery systems that are not affected by the aqueousvaginal discharge in the vagina and food transport in the esophagus, inpart because of its good adhesion to the vaginal and esophageal liningsto provide predictably modulated release of the drug. The need for sucha novel drug delivery system prompted the pursuit of the study, subjectof the present invention.

Accordingly, the invention is directed to a new class ofpolyether-ester-urethane-based compositions comprising at least onecrystalline amphiphilic absorbable polyether-ester-urethane and at leastone bioactive agent dissolved in a liquid derivative of a polyalkyleneglycol. The chemical composition of the polyether-ester-urethane (PEEU),polyalkylene glycol derivative, and the bioactive agents and theirrelative concentrations in these compositions can be controlled toachieve balanced properties so as to (1) provide the proper viscosity toallow their facile delivery to the application site using existingdeployment equipment or modifications thereof; (2) allow a timelyhydroformation (i.e., phase separation in the presence of an aqueousenvironment, as in biological sites) into tissue adhering liner (orcover) that is biomechanically compatible with the lining of bodycavities or canals as in the case of the vagina, esophagus, and bloodvessels—hydroformation is effected by the migration of the polymericsolvent (with simultaneous phase separation of the PEEU to form a liner)and liner adhesion to the interior surface of the luminal wall ispromoted by the highly hydrophilic polyether component of thepolyether-ester-urethane; (3) form a crystalline liner exhibitingresilience and controlled dimensional stability by virtue of thesegmented amphiphilic nature of the PEEU chain and the presence ofquasi-crosslinks (presented by the crystalline fraction and associationof the urethane segments), respectively; (4) be loaded with at least onetype of bioactive agent, depending on the intended use of the bioactivecompositions by virtue of having components which can be selected todissolve or disperse a broad range of bioactive agents exhibitingdifferent solubility parameters; and (5) allow achieving controllablerelease profiles of the different bioactive agents at the applicationsites by virtue of having PEEU compositions capable of having variablehydrophilic/hydrophobic ratios to be in concert with the desired modesof drug release. Further illustrations of the present invention areprovided by the following examples:

EXAMPLE 1 Synthesis and Characterization of an Absorbable, CrystallinePolyether-ester-Urethane (C-PU): General Method

For an initial charge, poly(ethylene glycol) (PEG-1000) (M_(w)=1000 Da)was added to a 250 mL, 2-neck, round-bottom flask. The contents wereheated at 100° C. under reduced pressure for 1 hour and then purged withdry nitrogen. A mechanical stir rod was installed with a Teflon bearingassembly and the contents were heated to 100° C.-110° C. while stirring.A second charge, consisting of 1-lactide and glycolide was added andstirred at 120 RPM until the reaction mixture achieved one phase. Athird charge, Tin(II) 2-ethyl hexanoate, was then added in a 0.2Msolution in toluene. The reaction solution was then heated at 100° C.until near complete monomer conversion was achieved. The polymer wasthen cooled to 100° C. and diisocyanatohexane was added. The solutionwas then stirred at 100° C. for at least one hour until the isocyanatereacted completely. After interlinking the polymer was heated at 100° C.for 2.5-3.0 hours and then was dissolved at 55-67° C. in tetrahydrofuran(THF). After dissolution of the polymer in the THF, 2-propanol was addedto react with any isocyanate end-groups and the solution was stirred for1 hour. The resulting polymer was isolated by evaporating the solventunder reduced pressure and characterized for identity (IR), molecularweight (GPC), and thermal properties (DSC).

EXAMPLE 2 Synthesis and Characterization of Two Typical Absorbable,Crystalline Polyether-Ester-Urethanes, C-PU-1 and C-PU-2

Poly-ester-urethanes C-PU-1 and C-PU-2 were prepared using the method ofExample 1. The poly(ethylene glycol) used in C-PU-1 and C-PU-2 had amolecular weight of 1000 Dalton. For Poly-ester-urethanes C-PU-1 andC-PU-2, 0.025 and 0.025 moles of poly(ethylene glycol), 0.46 and 0.48moles of 1-lactide, 0.08 and 0.05 moles of glycolide, 6.71×10⁻⁵ and6.64×10⁻⁵ moles of tin(II) 2-ethyl hexanoate, and 0.017 and 0.017 molesof 1,6-diisocyanatohexane were used, respectively. Polymers C-PU-1 andC-PU-2 were characterized for molecular weight by GPC usingdichloromethane as the mobile phase which resulted in M_(n) of 18 and 22kDa, M_(w) of 38 and 133 kDa, Mp of 24 and 63 kDa, and PDI of 2.2 and6.1, respectively. Six mg samples of C-PU-1 and C-PU-2 were annealed in5 mL glass vials submerged in a 70° C. oil bath for 1.75 hours,equilibrated in the DSC apparatus for 5 minutes at 20° C. upon removalfrom the bath, and heated to 220° C. at a rate of 20° C./min todetermine the thermal properties. This resulted in meltingtemperatures/heats of fusion (T_(m),/ΔH) of 90.9° C./7.9 J/g and 92.5°C./16.3 J/g for C-PU-1 and C-PU-2 respectively.

Although the present invention has been described in connection with thepreferred embodiments, it is to be understood that modifications andvariations may be utilized without departing from the principles andscope of the invention, as those skilled in the art will readilyunderstand. Accordingly, such modifications may be practiced within thescope of the following claims. Moreover, Applicant hereby discloses allsubranges of all ranges disclosed herein. These subranges are alsouseful in carrying out the present invention.

What is claimed is:
 1. A bioactive hydroforming luminal linercomposition comprising: at least one absorbable crystalline amphiphilicpolyether-ester-urethane comprising at least one polyalkylene glycolend-grafted with at least one cyclic monomer selected from the groupconsisting of ε-caprolactone, p-dioxanone, a lactide, glycolide,1,5dioxapan-2-one, trimethylene carbonate, and a morpholinedione to forman end-grafted product, wherein polyether-ester is interlinked with adiisocyanate to form a polyether-ester-urethane with an alternatingstructure (C-[A-B-A])m, wherein C is derived from the diisocyanate, A isthe polyester, and B is the polyether, wherein the molar ratio of cyclicmonomer to polyalkylene glycol is about 20:1, the molar ratio ofpolyalkylene glycol to diisocyanate is about 1.5:1, and any unreactedisocyanate group is converted to a urethane group through reaction withan aliphatic alcohol, said polyether-ester-urethane having a molecularweight of at least 10 kDa and a heat of fusion greater than 5 J/g; aliquid derivative of a polyether glycol; and at least one bioactiveagent selected from the group consisting of antimicrobial,antiretroviral, antiviral, antiretroviral, anti-inflammatory,antiproliferative, immunosuppressing, antineoplastic, and anestheticagents.
 2. A bioactive hydroforming luminal liner composition as inclaim 1 wherein the absorbable crystalline polyether-ester-urethanecomprises a polyethylene glycol having a molecular weight of 3 to 35 kDaend-grafted with at least one cyclic monomer selected from the groupconsisting of ε-caprolactone, p-dioxanone, a lactide, glycolide,1,5dioxapan-2-one, trimethylene carbonate, and a morpholinedione, andfurther interlinked with at least one aliphatic diisocyanate selectedfrom the group consisting of 1,4-tetramethylene diisocyanate,1,4-bis(methylene isocyanato) cyclohexane, 1,6-hexamethylenediisocyanate, and lysine diisocyanate, wherein any unreacted isocyanateis converted to a urethane group through reaction with 2-propanol.
 3. Abioactive absorbable hydroforming luminal liner composition as in claim1 wherein the at least one bioactive agent comprises an antifungal agentselected from the group consisting of ketoconazole, miconazole,voriconazole, and fluconazole.
 4. A bioactive hydroforming luminal linercomposition as in claim 1 wherein the at least one liquid derivative ofa polyether glycol is selected from the group consisting of acylatedpolyethylene glycol, benzylated polyethylene glycol, o-alkylatedpolyethylene glycol, o-benzylated polyethylene glycol, acylatedcopolymers of ethylene and propylene oxide, benzylated copolymer ofethylene and propylene oxide and benzylated copolymer of ethylene andpropylene oxide.
 5. A bioactive, hydroforming luminal liner compositionas in claim 3 as an antifungal formulation for treating yeast infectionin humans, the yeast infections selected from the group consisting ofvaginal yeast infections and esophageal yeast infections.
 6. Abioactive, hydroforming luminal liner composition as in claim 1 whereinthe at least one bioactive agent comprises an antibacterial agentselected from the group consisting of metronidazole, clindamycin,doxycycline, and tobramycin.
 7. A bioactive, hydroforming luminal linercomposition as in claim 6 as an antibacterial formulation for treatingbacterial infection in humans, the bacterial infections selected fromvaginal bacterial infections and esophageal bacterial infections.
 8. Abioactive, hydroforming luminal liner composition as in claim 5 furtherincluding an applicator kit for delivering the active formulationcomprising a solid applicator in a tubular housing of larger diameter,wherein the applicator has clockwise, helical grooves of about 2 mm inwidth and depth, and wherein both the applicator and tubular housing arethreaded at the ends to allow secure assembling of the kit.
 9. Abioactive, absorbable, hydroforming luminal liner composition as inclaim 5 further comprising a method of preparation, sterilization, andpackaging entailing the steps of: a) dissolving the crystallinepolyether-ester-urethane in the liquid derivative of a polyether glycol;b) heat-sterilizing the liquid solution; c) mixing the sterilized liquidsolution with the antifungal agent, under aseptic conditions; d)transferring an aliquot of active formulation from step “c” to apre-sterilized plastic tubular housing of the applicator and securingthe applicator in a housing; e) placing the assembled applicator kitfrom step “d” in a sealable clear plastic pouch; f) heat-sealing theplastic pouch from step “e.”.
 10. A bioactive, absorbable, hydroformingluminal liner composition as in claim 6 further comprising a method ofpreparation, sterilization, and packaging entailing the steps of: a)dissolving the crystalline polyether-ester-urethane in the liquidderivative of a polyether glycol; b) heat-sterilizing the liquidsolution; c) mixing the sterilized liquid solution with theantibacterial agent, under aseptic conditions; d) transferring analiquot of active formulation from step “c” to a pre-sterilized plastictubular housing of the applicator and securing the applicator in ahousing; e) placing the assembled applicator kit from step “d” in asealable clear plastic pouch; f) heat-sealing the plastic pouch fromstep “e.”.
 11. A bioactive, hydroforming luminal liner composition as inclaim 8 further including a method for application of said antifungalformulation onto the mucosal lining of the vagina of a human entailingthe steps of a) removing the applicator loaded with the liquiddrug-loaded formulation; b) inserting the applicator into the vaginalcanal using a clockwise, inward movement; and c) removing the applicatorfrom the vaginal canal using a counter-clockwise, outward movement. 12.A bioactive hydroforming luminal liner composition as in claim 1 whereinthe polyalkylene glycol is polyethylene glycol, the at least one cyclicmonomer is selected from the group consisting of a lactide andglycolide, the molar ratio of cyclic monomer to polyalkylene glycol is21.6:1, the molar ratio of polyethylene glycol to diisocyanate is1.47:1, and any unreacted isocyanate group is converted to a urethanegroup through reaction with an aliphatic alcohol.